Calcium metabolism anticonvulsants

Long-term anticonvulsive therapy with diphenylhydantoin or phenobarbital is known to cause osteomalacia by influencing calcium metabolism (24,25). Alteration in the metabolism of vitamin D, presumably secondary to induction of hepatic microsomal enzymes, leads to the calcium and bone abnormalities (26). Patients on anticonvulsive therapy with phenytoin exhibit a decrease in serum 25-hydroxyvitamin D (27). Adequate dietary amounts of vitamin precursors or microsomal enzyme stimulators might prevent these effects of long-term therapy. 

The enzyme-inducing effects of phenytoin and other anticonvulsants increase the metabolism of the vitamin D, thereby reducing its effects and disturbing calcium metabolism. In addition, phenytoin may possibly reduce the absorption of calcium from the gut. ... 

The disturbance of calcium metabolism by phenytoin and other anticonvulsants is very well established, but there are only a few reports describing a poor response to vitamin D. The effects of concurrent treatment should be well monitored. Those who need vitamin D supplements may possibly need greater than usual doses. 

Hunter J, Maxwell JD, Stewart DA, Parson V, Williams R. Altered calcium metabolism in epileptic children on anticonvulsants. BMJ (1971) 4,202-4. 

Anticonvulsant Drugs and Calcium Metabolism," Nutrition Reviews, Vol. 33,1975, pp. 221-222. 

Regarding the effect of anticonvulsants on calcium metabolism, the potential size of the problem was highlighted by Richens and Rowe (34 ) who showed that 22.5% of epileptic patients in an adult residential centre had decreased serum calcium levels, and 29% had increased alkaline phosphatase levels. Lemaire et al. (24 ) studied a case of osteomalacia due to anticonvulsants using tritium-labelled vitamin D. It was shown that its metabolism was accelerated in comparison with deficiency type osteomalacia. This supports the hypothesis that anticonvulsants, acting via hepatic enzyme induction processes, cause increased transformation of vitamin D into inactive metabolites. Richens states that it is likely that anticonvulsant osteomalacia is caused by a disturbance of the hepatic hydroxylation of vitamin D3 to... 

All anticonvulsants (except gabapentin), atypical antipsychotics, benzodiazepines, and calcium channel blockers require liver metabolism, and dosage adjustments may be needed (e.g., 25-50% reduction of normal doses) Carbamazepine or oxcarbazepine Alternative lamotrigine Acute mania or mixed episode first choice lithium... 

Latham AN, Millbank L, Riehens A, Rowe DJF Liver en me induction by anticonvulsant drugs, and its relationship to disturbed calcium and folic acid metabolism. J CUn Pharmacol (1973)13,337- 2. 

A condition in which there is decalcification of bone tissue. It occurs when there is reduced calcium or vitamin D intake, for instance in malabsorption. Osteomalacia can also occur as a result of treatment with anticonvulsant drugs which are thought to interfere with the metabolism of vitamin D. Low serum calcium levels occur along with high serum alkaline phosphatase levels, the latter being due to a secondary increase in osteoblastic activity. 

An anticonvulsant drug. Among its undesirable side-effects h that of osteomalacia. This is thought to be due to the stimulatior by the drug of hepatic enzymes which inactivate vitamin D resulting in decreased calcium absorption. Phenytoin also in terferes with folate metabolism and this may result in i megaloblastic anaemia. 

Before leaving the subject of calcium homeostasis, it is perhaps worth mentioning that some inducers of the hepatic hydroxylating enzymes involved in detoxication (see below) can cause osteomalacia on chronic administration. Such enzyme inducers include the antioxidant ethoxyquin and some anticonvulsant drugs. Their mode of action is far from clear but possibly results from their effects on metabolism of vitamin D in the liver. 

Calcium absorption was studied in 28 adult male epileptics on chronic anticonvulsant therapy. In 16 patients on phenytoin alone calcium absorption was abnormal in 9. In 12 patients on both phenytoin and phenobarbitone calcium absorption was abnormal in 3. Hypocalcaemia (<8.5 mg/ 100 ml) occurred in only 2 patients, while serum alkaline phosphatase was elevated in 7 patients. The findings support the suggestion that rickets and osteomalacia reported in patients on chronic anticonvulsant therapy results from reduced calcium absorpion. The effect of these drugs appear to be the increased metabolism of vitamin D via enzyme induction, and an increase in the excretion of polar metabolites 25-hydroxycholecalciferol and 1,25-dihy-droxycholecalciferol which are necessary for normal calcium absorption (40 ). 

Stamp et al, (48 ) suggested that plasma calcium concentrations among epileptics may be regulated by effects of anticonvulsants on mechanisms other than those concerning vitamin D, i.e. that it is not related to hepatic induction of vitamin D-metabolizing enzymes as has been thought. 

Stamp, T. C. B., Round, J. M., Dupre, P. et al. (1976) Enzyme induction and calcium and vitamin D metabolism during chronic anticonvulsant therapy. In Anticonvulsant Drugs and Enzyme Induction, p. 87. Associated Scientific Publishers, Amsterdam. 

---